PuSH - Publication Server of Helmholtz Zentrum München

Erdmann, J.* ; Stark, K.* ; Esslinger, U.B.* ; Rumpf, P.M.* ; Koesling, D.* ; de Wit, C.* ; Kaiser, F.J.* ; Braunholz, D.* ; Medack, A.* ; Fischer, M.* ; Zimmermann, M.E.* ; Tennstedt, S.* ; Graf, E. ; Eck, S. ; Aherrahrou, Z* ; Nahrstaedt, J.* ; Willenborg, C.* ; Bruse, P.* ; Brænne, I.* ; Nöthen, M.M.* ; Hofmann, P.* ; Braund, P.S.* ; Mergia, E.* ; Reinhard, W.* ; Burgdorf, C.* ; Schreiber, S.* ; Balmforth, A.J.* ; Hall, A.S.* ; Bertram, L.* ; Steinhagen-Thiessen, E.* ; Li, S.C.* ; Marz, W.* ; Reilly, M.* ; Kathiresan, S.* ; McPherson, R.* ; Walter, U.* ; CARDIoGRAM Consortium (Wichmann, H.-E. ; Döring, A. ; Illig, T. ; Klopp, N. ; Meisinger, C. ; Peters, A.) ; Ott, J.* ; Samani, N.J.* ; Strom, T.M. ; Meitinger, T. ; Hengstenberg, C.* ; Schunkert, H.*

Dysfunctional nitric oxide signalling increases risk of myocardial infarction.

Nature 504, 432-436 (2013)
Publ. Version/Full Text Volltext DOI
Open Access Green as soon as Postprint is submitted to ZB.
Myocardial infarction, a leading cause of death in the Western world, usually occurs when the fibrous cap overlying an atherosclerotic plaque in a coronary artery ruptures. The resulting exposure of blood to the atherosclerotic material then triggers thrombus formation, which occludes the artery. The importance of genetic predisposition to coronary artery disease and myocardial infarction is best documented by the predictive value of a positive family history. Next-generation sequencing in families with several affected individuals has revolutionized mutation identification. Here we report the segregation of two private, heterozygous mutations in two functionally related genes, GUCY1A3 (p.Leu163Phefs*24) and CCT7 (p.Ser525Leu), in an extended myocardial infarction family. GUCY1A3 encodes the α1 subunit of soluble guanylyl cyclase (α1-sGC), and CCT7 encodes CCTη, a member of the tailless complex polypeptide 1 ring complex, which, among other functions, stabilizes soluble guanylyl cyclase. After stimulation with nitric oxide, soluble guanylyl cyclase generates cGMP, which induces vasodilation and inhibits platelet activation. We demonstrate in vitro that mutations in both GUCY1A3 and CCT7 severely reduce α1-sGC as well as β1-sGC protein content, and impair soluble guanylyl cyclase activity. Moreover, platelets from digenic mutation carriers contained less soluble guanylyl cyclase protein and consequently displayed reduced nitric-oxide-induced cGMP formation. Mice deficient in α1-sGC protein displayed accelerated thrombus formation in the microcirculation after local trauma. Starting with a severely affected family, we have identified a link between impaired soluble-guanylyl-cyclase-dependent nitric oxide signalling and myocardial infarction risk, possibly through accelerated thrombus formation. Reversing this defect may provide a new therapeutic target for reducing the risk of myocardial infarction.
Additional Metrics?
Edit extra informations Login
Publication type Article: Journal article
Document type Scientific Article
Keywords Coronary-artery-disease ; Soluble Guanylate-cyclase ; Genome-wide Association ; Susceptibility Loci ; Adults
ISSN (print) / ISBN 0028-0836
e-ISSN 1476-4687
Journal Nature
Quellenangaben Volume: 504, Issue: 7480, Pages: 432-436 Article Number: , Supplement: ,
Publisher Nature Publishing Group
Publishing Place London
Reviewing status Peer reviewed